The present invention relates to a method for resolving a racemic alcohol and, more particularly, to a method for resolving a racemic alcohol into its two antipodes using an enzymatic reaction in an organic solvent with high selectivity and efficiency.
Heretofore, as an optical resolution of a racemic alcohol via an esterification using an enzyme are known a process for reacting a racemic alcohol with a carboxylic acid, that is, a process using a so-called esterification, a process using an interesterification between a racemic alcohol and a carboxylic acid ester, and so on.
Since it is difficult to carry out the process using the esterification in an aqueous system because a hydrolysis of an ester formed occurs predominantly, it is reported that it is carried out in an organic solvent [J. Am. Chem. Soc., 107, 7072 (1985)]. In this example, however, it is reported that a gel substance is formed as a result of dissolution of an organic solvent-insoluble enzyme in water formed in the system, thereby leading to an insufficient recovery of the enzyme after the completion of the reaction. It further suffers from the disadvantages that the reaction proceeds slowly and that a yield and a purity of an optically active substance are not always sufficient. Accordingly, a reaction such as using an organic solvent-insoluble enzyme in an organic solvent is said to be inappropriate. The interesterification as another process for the optical resolution of the racemic alcohol may be represented in the following reaction scheme: ##STR1## wherein R.sup.1 and R.sup.3 each is a residue of an alcohol, and
R.sup.2 is a residue of a carboxylic acid.
As this reaction is an equilibrium reaction, it is extremely difficult to thoroughly convert the starting material to the reaction product so that this interesterification suffers from the disadvantage that a reaction takes a long period of time.
This tendency arises to an increased extent in instances where a secondary alcohol or a tertiary alcohol, each having a large degree of a steric hindrance, is used as a racemic alcohol.
In order to overcome these disadvantages, processes have been proposed in which there are used an ester such as a trihaloethanol ester having a large steric hindrance, alcohol moiety [(J. Am. Chem.: 107, 7072 (1985); Tetrahedron Letters: 28, 2091 (1987)] and a diacylglycerin ester, [Tetrahedron Letters: 27, 29 (1986)]. These processes present the advantage that the interesterification can proceed to some extent toward the right side in the above reaction scheme, however, they still require long reaction times. In particular, in instances where the racemic alcohol is the secondary or tertiary alcohol, this process still suffers from the advantages that a degree of the completion of the reaction is insufficient and that the corresponding optically active product cannot be synthesized efficiently.
Heretofore, the esterification of an alcohol with an acid anhydride using a catalyst such as an acid or a base without the use of any enzyme is known. However, this type of reaction is substantially infeasible to control a stereo selectively of a chemical product. There are disclosed an example using an open-chain acid anhydride [W. W. Prichard: Org. Syn. Coll., Vol. 3, 452 (1955)] and an example using a cyclic acid anhydride [A. C. Cope.: Org. Syn., Coll.: Vol. 4, 304 (1963)].
In a conventional reaction system using an enzyme as a catalyst, it is extremely disadvantageous to carry out the esterification because the acid anhydride that is an acylating agent undergoes the hydrolysis due to water in the system using a water-soluble enzyme in an aqueous solution and the acylating agent is converted to the free carboxylic acid.
Furthermore, as an example of synthesizing an ester by means of the interesterification with an enol ester of a carboxylic acid utilizing an irreversible reaction, there is known an acylation of an alcohol with isopropenyl acetate using as a catalyst a strong acid such as p-toluenesulfonic acid or sulfuric acid [Ind. Eng. Chem.: 41(12), 2920(1949)]. This method requires severe conditions for reaction so that an unstable substance cannot be used as a starting material and it is extremely difficult to use this method for synthesizing an optically active substance.